Background

In 1909, Hyde and Montgomery[1] first described prurigo nodularis as pruritic nodules on the extensor surfaces of the lower extremities in middle-aged women. Prurigo nodularis can be a bothersome-to-debilitating disease, usually seen as multiple, intensely pruritic, excoriated nodules erupting on the extensor surfaces of the limbs secondary to itching or rubbing. In current practice, prurigo nodularis is still a condition of unknown etiology. Many conditions have been reported to induce prurigo nodularis, from internal malignancy to renal failure to psychiatric conditions.

Pathophysiology

Chronic mechanical trauma to the skin causes thickening of the skin proportionate to the trauma. Repetitive rubbing, scratching, and touching (induced by a foreign body or self-induced) results in plaques or nodular lichenification and hyperkeratosis. Pigmentary changes often result from such repetitive trauma to the skin.

With prurigo nodularis, a person feels intense pruritus at discrete points and cannot control the urge to rub or scratch these points on the body. Any abnormality or explanation for the pruritus is unknown; scratching by the individuals who are affected is obvious. The results are discrete, nodular, hyperpigmented/purpuric lesions with surfaces that are scaly, excoriated, and possibly crusted.

Immunohistochemical studies demonstrate increased numbers of dermal nerve fibers in prurigo nodularis. The sensation of pruritus is transmitted mainly by thin, unmyelinated epidermal nerves. Lesional and uninvolved prurigo nodularis skin biopsies showed significantly decreased intraepidermal nerve fiber density, suggesting the presence of a subclinical small fiber neuropathy in prurigo nodularis.[2] Another study indicated that Th2 cytokines related to STAT6 activation together with some unknown stimuli that activate STAT3 play a principal role in the pathogenesis of prurigo nodularis.[3]

Epidemiology

Mortality/Morbidity

Prurigo nodularis is benign and does not increase mortality; however, severe morbidity can occur in untreated and even in some treated persons who are affected. Pruritus and the extent of body surface area involved become so great for some patients that they no longer feel functional for work or other everyday activities.

Some conditions associated with prurigo nodularis may cause mortality. Prurigo nodularis has been documented to be much more common in immunocompromised and HIV populations. The positive predictive value (PPV) for HIV positivity was 36% for prurigo nodularis in a study from French Guiana. The PPV for having a CD4 lymphocyte count of less than 200/mcL was 72% for prurigo nodularis. Prurigo nodularis was thus predictive of advanced immunosuppression, and, in the absence of facilities to perform a CD4 count, this study suggests that HIV antiretrovirals should be initiated for patients with prurigo nodularis in third world countries.[4]

Some cases of prurigo nodularis are associated with internal malignancy. Hodgkin disease (lymphoma) may present with pruritus and lichenified nodules.[5] Prurigo nodularis may be the first manifestation of chronic autoimmune cholestatic hepatitis[6] and may be seen with severely decreased kidney function and uremic pruritus.

Race

No racial disparity is known for prurigo nodularis.

Sex

Women were formerly believed to have a disproportionate amount of prurigo nodularis compared to men; however, no documented difference exists in frequency between the sexes.

Age

Prurigo nodularis can occur at any age, but it most often occurs in middle-aged and older persons.

History

Prurigo nodularis patients are most often middle-aged to elderly. Patients with prurigo nodularis invariably complain of a long-standing history of severe, unremitting pruritus. Patients can point out specific sites where they began feeling itchy and where dark-colored nodules formed soon after. Mature nodules rarely increase or decrease in size; spontaneous resolution is even more rare. Prurigo nodularis is usually bilaterally symmetric, with nodules that are either stable or increasing in number.

The patient's medical history may be significant for several conditions, as follows:

Hepatic or renal dysfunction

Local trauma or insult to the skin

Infection

HIV/immunodeficiency[7]

Anxiety or other psychiatric condition

Patients may have no significant medical or psychiatric history. The patient's history often reveals a long list of over-the-counter and/or prescribed medications (topical and oral), which usually have produced little or no relief of symptoms. Up to 80% of patients have a personal or family history of atopic dermatitis, asthma, or hay fever (compared with approximately 25% of the normal population).

Physical

Prurigo nodularis nodules or papules are 3-20 mm in diameter; they are discrete, scaly, generally symmetric, hyperpigmented or purpuric, and firm. Nodules and papules occur on the extensor surfaces of the arms, the legs, and sometimes the trunk.

Prurigo nodularis lesions may show signs of excoriation with flat, umbilicated, or crusted top. Lesions may number from 1-2 to hundreds. The nodule pattern may be follicular. Upon entering the examination room and while patients' describe the locations of the lesions, patients may scratch or rub the lesions rather than pointing to them. Many prurigo nodularis patients appear very anxious, worried, or even obsessed with the nodules. Note the images below.

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Prurigo nodularis. Courtesy of Jeffrey Meffert, MD.

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Prurigo nodularis. Courtesy of Jeffrey Meffert, MD.

Causes

The cause of prurigo nodularis is still unknown. Many associated conditions are known, but their roles as coexisting or preexisting conditions have not been established in causing prurigo nodularis. Notable changes in papules and nodules are increased in certain inflammatory cell types, inflammatory products, and neural hyperplasia.

Mast cells and neutrophils are seen in higher-than-normal levels in prurigo nodularis; however, their degranulation products are not increased. Eosinophils are not seen in higher numbers; however, the protein granule products (ie, major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin) are seen in significantly higher levels.

Papillary dermal nerves and Merkel cells are sensory nerves found in the dermis and the epidermis, respectively.[8] They are both found in increased numbers in prurigo nodularis. These are neural receptors that sense touch, temperature, pain, and itch. These increases in sensory nerves are not seen in lichen simplex chronicus, another pruritic disease that causes epidermal hyperplasia but in a plaquelike morphology.

Calcitonin gene–related peptide and substance P immunoreactive nerves are markedly increased in prurigo nodularis skin compared with normal skin.[9] These neuropeptides may mediate the cutaneous neurogenic inflammation and pruritus in prurigo nodularis. In addition, the capsaicin-binding nonselective cation channel known as vanilloid receptor subtype 1 has highly increased expression in epidermal keratinocytes and nerve fibers in prurigo nodularis lesions, but these can be normalized with capsaicin application.

Hepatitis C, mycobacteria,[10, 11, 12] Helicobacter pylori, Strongyloides stercoralis,[13] and HIV have been reported as infectious etiologies of prurigo nodularis or as associated with prurigo nodularis in case reports or from single-center studies.

Interleukin 31, a T-cell–derived cytokine that causes severe pruritus and dermatitis in transgenic mice, is elevated in individuals with prurigo nodularis.[14] Interleukin 31 expression in atopic individuals is also rapidly induced by staphylococcal superantigen; however, the link between these findings has not been extensively researched.

Histologic Findings

The histologic features of prurigo nodularis[17] include a hyperkeratotic epidermis with acanthosis and parakeratosis. Rete ridges are elongated and irregular with a dense dermal infiltrate consisting of neutrophils, eosinophils, histiocytes, and monocytes.[18] Also notable in the dermis are thickened nerve fibers and fibrosis with thickened collagen bundles. Thickened nerve fibers are dilated on electron microscopy. Schwann cells show vacuolization and degeneration with no detectable mitochondria. Axons and Schwann cells both show hyperproliferation.[17, 19]

Highly characteristic for prurigo nodularis is the presence of thick, compact orthohyperkeratosis; irregular epidermal hyperplasia or pseudoepitheliomatous hyperplasia; focal parakeratosis or superficial epithelial necrosis; hypergranulosis; fibrosis of the papillary dermis with vertically arranged collagen fibers; increased number of fibroblasts and capillaries; a superficial, perivascular and/or interstitial inflammatory infiltrate of lymphocytes, macrophages and, to a lesser extent, eosinophils and neutrophils. Correlation of clinical and histological findings is necessary to reliably distinguish between prurigo nodularis and lichen simplex chronicus,[20] although both disorders may coexist in the same patient and both are a reaction to rubbing or scratching the skin.

Medical Care

Current available treatments of prurigo nodularis have had mild-to-moderate success at best. Often, combinations of several medications or physical modalities may be used in an attempt to control this process.

Topical, oral, and intralesional corticosteroids have all been used in prurigo nodularis in attempts to decrease inflammation and sense of itching and to soften and smooth out firm nodules. The improvement with corticosteroids is variable, and corticosteroids are sometimes not helpful. Intralesional corticosteroid (usually triamcinolone acetonide) treatment is commonly used in resistant cases of limited extent. Triamcinolone acetonide concentrations as low as 2.5 mg/mL may be effective, although more scarred pruriginous lesions may require higher concentrations. A total dose of 20 mg (8 mL of 2.5 mg/mL) for adults every 3-4 weeks is safe for patients without diabetes mellitus or hypertension. An 8-am serum cortisol test can be performed if concerns exist about adrenal suppression.[21]

Menthol, phenol, pramoxine, capsaicin cream,[22, 23] vitamin D-3 ointment,[24] and topical anesthetics are some other topical agents used to reduce pruritus. Treatment with DuoDerm or other occlusive therapies has been suggested to flatten lesions while at the same time preventing patients from directly scratching nodules.[25]

UV light treatment using UV-B[26] or UV-A plus psoralen may be beneficial for severe pruritus. Consider the adverse effects of prolonged UV exposure before such treatment. Monochromatic 308-nm light therapy may be helpful for recalcitrant lesions,[27] although this modality may be more useful in atopic dermatitis.[28] . The combination of UVB 308-nm excimer light and bath PUVA therapy may be effective in the treatment of prurigo nodularis.[29] UV-A1 has also been reported to benefit lichen simplex chronicus and prurigo nodularis.[30]

Antihistamines, anxiolytics, opiate receptor antagonists, and (most recently) thalidomide are oral medications other than steroids used for prurigo nodularis. Thalidomide[31, 32, 33] has been shown to aid in several severe dermatoses, including prurigo nodularis with or without associated HIV disease.[26, 34, 35] Severe teratogenic effects are well known and documented, and all women of childbearing age should be on adequate birth control methods. Patients taking thalidomide have an increased risk of peripheral neuropathy and sedation is common.

For steroid unresponsive patients or those with lesions on thin skin, a few case reports and small studies have shown efficacy of the topical immunomodulators tacrolimus and pimecrolimus.

Anecdotally, gabapentin has been reported to benefit lichen simplex chronicus and prurigo nodularis for some cases.[36, 37] Sedation is the main problem with this generic medication.

Habit reversal therapy for the itch-scratch cycle associated with prurigo nodularis may be helpful and can be administered by dermatology nurses trained in this therapy.[38]

Substance P (SP) is a major mediator of pruritus. It binds to the neurokinin receptor 1 (NKR1). The NKR1 antagonist aprepitant is marketed for prevention of chemotherapy-induced nausea and vomiting and for prevention of postoperative nausea and vomiting and may benefit patients with prurigo nodularis.[39]

Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus. Kappa-opioid receptors agonists bind to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. Nalfurafine, a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan.[40]

Surgical Care

Cryotherapy with liquid nitrogen helps reduce pruritus and flatten lesions.[41, 42] This modality can be particularly helpful in upper limb and trunk lesions for patients with diabetes mellitus or in patients with hypertension to minimize adverse effects of intralesional and highly potent topical corticosteroids. Thirty-second thaw cycles with 2-4 treatments are recommended, depending on the size of the lesion. Understanding the risks of scarring and change in pigmentation (especially in darker-skinned individuals) is important. Cryotherapy may be combined with other modalities (eg, intralesional corticosteroids).

Pulsed dye laser therapy may help reduce the vascularity of individual lesions.

Consultations

Pay special attention to patients with prurigo nodularis. Take a careful history of immune compromise or other internal disease. Refer patients to an internist or a family physician for possible further investigation and examination. Some patients benefit from psychiatric referral once underlying dermatologic and medical disorders have been excluded.[43]

Medication Summary

The goal of pharmacotherapy for prurigo nodularis is to break the itch-scratch-itch cycle by reducing pruritus, rubbing, picking, and scratching. One should always consider and rule out treatable endogenous and exogenous causes of pruritus.

Intramuscular injection may be used for widespread skin disorder, or intralesional injections may be used for localized skin disorder. Consider limiting total monthly dose to 20 mg to ensure HPA axis will not be suppressed.

Can cause severe, life-threatening birth defects and is contraindicated in pregnant women. Also contraindicated in women of childbearing potential unless using 2 forms of reliable contraception and complying with serial pregnancy testing while on therapy.

Also contraindicated in sexually active men not using latex condom as barrier contraception. Drug available only under special restricted distribution program called STEPS (System for Thalidomide Education and Prescribing Safety) Program; only prescribers and pharmacists registered with this program may prescribe and dispense thalidomide. For more information, contact the Celgene Corporation at 1-888-423-5436.

Class Summary

Tacrolimus ointment (Protopic)

Clinical Context:
Mechanism of action in prurigo nodularis not known. Reduces itching and inflammation by suppressing release of cytokines from T cells. Also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in early stages of T-cell activation. Additionally, may inhibit release of preformed mediators from skin mast cells and basophils and down-regulate expression of FCeRI on Langerhans cells. Can be used in patients as young as 2 y. Drugs of this class are more expensive than topical corticosteroids. Available as ointment in concentrations of 0.03 and 0.1%. Indicated only after other treatment options have failed.

OnabotulinumtoxinA (BOTOX®)

Clinical Context:
One of several toxins produced by Clostridium botulinum. Blocks neuromuscular transmission through a 3-step process, as follows: (1) blockade of neuromuscular transmission; botulinum toxin type A (BTA) binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals. (2) BTA is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal. (3) BTA blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. Toxin does not affect synthesis or storage of acetylcholine or conduction of electrical signals along the nerve fiber. Prevents calcium-dependent release of acetylcholine and produces a state of denervation at the neuromuscular junction and postganglionic sympathetic cholinergic nerves in the sweat glands.

Typically, a 24-72 h delay between administration of toxin and onset of clinical effects exists, which terminate in 2-6 mo.

This purified neurotoxin complex is a vacuum-dried form of purified BTA, which contains 5 ng of neurotoxin complex protein per 100 U.

BTA has to be reconstituted with 2 mL of 0.9% sodium chloride diluent. With this solution each 0.1 mL results in 5 U dose. Patient should receive 5-10 injections per visit.

Must be reconstituted from vacuum-dried toxin into 0.9% sterile saline without preservative using manufacturer's instructions to provide injection volume of 0.1 mL; must be used within 4 h of storage in refrigerator at 2-8°C.

Preconstituted dry powder must be stored in freezer at < 5°C.

Injections of botulinum toxin must be repeated at varying intervals to maintain long-term results.

Complications

Prognosis

The prognosis for spontaneous remission of prurigo nodularis is not good. Once prurigo nodularis lesions occur, complete resolution of lesions is uncommon. Most lesions remain present in some form even after long-term treatment. At this time, treating more than just the most symptomatic lesions is difficult. Considerable time is usually required to slow or stop the itch/scratch cycle so that the lesions resolve.

Ultimately, a strong therapeutic alliance is the best outcome predictor because the course of the disease is long, with waxing and waning symptoms, making the patient prone to being subjected to excessive diagnostic procedures and to seek alternative therapies.